scholarly journals Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

Author(s):  
Pooja Patel ◽  
Arielys Mendoza ◽  
Dexter J. Robichaux ◽  
Meng C. Wang ◽  
Xander H. T. Wehrens ◽  
...  

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.

2012 ◽  
Vol 207 (9) ◽  
pp. 1406-1415 ◽  
Author(s):  
Young Ran Kim ◽  
Shee Eun Lee ◽  
In-Chol Kang ◽  
Kwang Il Nam ◽  
Hyon E. Choy ◽  
...  

BMB Reports ◽  
2008 ◽  
Vol 41 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Song-Iy Han ◽  
Yong-Seok Kim ◽  
Tae-Hyoung Kim

2007 ◽  
Vol 27 (3) ◽  
pp. 354-361 ◽  
Author(s):  
Silvia Carloni ◽  
Andrea Carnevali ◽  
Mauro Cimino ◽  
Walter Balduini

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Jason Karch ◽  
Jennifer Q Kwong ◽  
Adam R Burr ◽  
Michelle A Sargent ◽  
John W Elrod ◽  
...  

A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death.


Autophagy ◽  
2010 ◽  
Vol 6 (8) ◽  
pp. 1157-1167 ◽  
Author(s):  
Ning Zhang ◽  
Yanfei Qi ◽  
Carol Wadham ◽  
Lijun Wang ◽  
Alessandra Warren ◽  
...  

2001 ◽  
Vol 8 (8) ◽  
pp. 829-840 ◽  
Author(s):  
G Denecker ◽  
D Vercammen ◽  
M Steemans ◽  
T Vanden Berghe ◽  
G Brouckaert ◽  
...  

1999 ◽  
Vol 276 (3) ◽  
pp. C717-C724 ◽  
Author(s):  
Michel Warny ◽  
Ciarán P. Kelly

Apoptosis is a physiological cell death that culminates in mitochondrial permeability transition and the activation of caspases, a family of cysteine proteases. Necrosis, in contrast, is a pathological cell death characterized by swelling of the cytoplasm and mitochondria and rapid plasma membrane disruption. Necrotic cell death has long been opposed to apoptosis, but it now appears that both pathways involve mitochondrial permeability transition, raising the question of what mediates necrotic cell death. In this study, we investigated mechanisms that promote necrosis induced by various stimuli ( Clostridium difficile toxins, Staphylococcus aureus alpha toxin, ouabain, nigericin) in THP-1 cells, a human monocytic cell line, and in monocytes. All stimuli induced typical features of necrosis and triggered protease-mediated release of interleukin-1β (IL-1β) and CD14 in both cell types. K+depletion was actively implicated in necrosis because substituting K+for Na+in the extracellular medium prevented morphological features of necrosis and IL-1β release. N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum caspase inhibitor, prevented morphological features of necrosis, plasma membrane destruction, loss of mitochondrial membrane potential, IL-1β release, and CD14 shedding induced by all stimuli. Thus, in monocytic cells, necrosis is a cell death pathway mediated by passive K+efflux and activation of caspase-like proteases.


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